Many tumors that resist or acquire resistance to current targeted therapies used in the clinic exhibit elevated surface levels of proteins such as c-Met. For example, lung cancer acquires resistance to EGF-R inhibitors such as Tarceva. Inhibitors like Tarceva are intended to block the activity of receptor tyrosine kinases (known as tyrosine kinase inhibitors, or TKI's), but the majority of cases do not respond to TK inhibition. These tumors are characterized by elevated levels of cell surface proteins (such as c-Met) and thus become excellent candidates for therapeutic approaches described herein which approaches can target the overexpressed proteins and penetrate tumor cells.
Current attempts are being made in the field to develop c-Met antibodies or inhibitors that are intended to block signaling through c-Met. However, past history indicates that the majority of cases will not respond to signal blocking antibodies or small molecules because the tumor adopts alternative means to continue proliferating despite signal inhibition.
The compositions described herein circumvent the need to block signaling by using a cell surface receptor (for example, c-Met) as a portal to deliver toxic molecules into the tumor cell and kill tumors from within. Ligand directed delivery enables the targeted binding to tumors that are positive for specific cell surface receptors (for example, c-Met) and the membrane penetration domain in the delivery molecule enables penetration and lysis across the endosomal membrane after cell surface receptor-mediated endocytosis. The delivery protein is also modified to non-covalently assemble with and transport certain therapeutic molecules through, for example, ionic interactions.